Potent Cyclooxygenase-2 Inhibitors Research Articles

Design, Synthesis and Biological Activities Evaluation of Novel Pterostilbene-urea Derivatives as Potential Anti- inflammatory Agents.

1. The toxicity of derivatives was removed by the reasonable modification of bioactive skeleton. 2. As potential COX-2 inhibitor with IC50 values ranging from 39.42 to 179.84 nM/L, compounds (Q4-Q10, Q20) exhibited superior anti-inflammatory activity at low micromolar concentrations. 3. Q7 (IC50 (COX-2)=61.05 nM/L), Q10 (IC50 (COX-2)=54.68 nM/L) and Q20 (IC50 (COX-2)=39.42 nM/L) showed stronger COX-2 inhibitory abilities than Celecoxib (IC50 (COX-2)=67.89 nM/L). 4. The strongest anti-inflammatory agent, Q20 (IC50 NO= 9.96 μM/L, IC50 (COX-2)=39.42 nM/L) effectively inhibited the secretion of IL-1β and TNF-α, exhibited the IC50 values of 12.30 and 9.07 μM/L respectively. 5. Q20 exerted as anti-inflammatory actives via targeting COX-2, down-regulating iNOS and TLR4 protein, and inhibiting the activation of NLRP3 inflammasome and NF-κB signal pathway.

Pharmacological investigations of newly synthesized oxazolones and imidazolones as COX-2 inhibitors

Oxazoles and Imidazoles are heterocyclic compounds with significant biological activities. The present study explores the pharmacological effects of some new oxazole and imidazole derivatives as potential COX-2 inhibitors. Docking studies of the compounds against targeted proteins COX-2 and TACE manifested good binding affinities for both the targets supporting their anti-inflammatory potential. Compounds (3F-A, 3F-B, N-A, N-B) were evaluated for in vivo anti-inflammatory effects by carrageenan-induced paw edema. Among all, compound N-A was found to be the most effective as it displayed most pronounced reduction in inflammation that was comparable to indomethacin. The in vivo tissue antioxidant activity was performed for estimation of the level of catalase, GSH, GST, and thiobarbituric acid in paw tissue. The results exhibited that targeted compounds improved the oxidative stress and restored the expression of enzymes. H &E staining revealed that aforesaid compounds displayed well-defined restoration of cellular damage. Compound NA exhibited maximum structural and functional preservation. Reduction in the expression of inflammatory markers was also analyzed by ELISA and maximum reduction in protein expression (COX-2 and TNF-a) was observed for compound N-B. Quantification of mRNA was done using PCR and a decrease in the expression of COX-2 mRNA level in treatment groups was depicted by all the new compounds but N-B showed maximum reduction in enzyme expression. All the results obtained from the present study have shown the significant anti-inflammatory potential of new compounds via the COX-2 inhibition pathway.

Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells

It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.

Rapid identifying of COX-2 inhibitors from turmeric (Curcuma longa) by bioaffinity ultrafiltration coupled with UPLC-Q Exactive-Orbitrap-MS and zebrafish-based in vivo validation

Turmeric (Curcuma longa), a typical source with recognized anti-inflammatory activity, is one such medicine-food homology source, yet its anti-inflammatory mechanisms and specific component combinations remain unclear. In this study, a net fishing method combining bio-affinity ultrafiltration and ultra-high performance liquid chromatography-mass spectrometry (AUF-LC/MS) was employed and 13 potential COX-2 inhibitors were screened out from C. longa. 5 of them (C1, 17, 20, 22, 25) were accurately isolated and identified. Initially, their IC50 values were measured (IC50 of C1, 17, 20, 22 and 25 is 55.08, 48.26, 29.13, 111.28 and 150.48 μM, respectively), and their downregulation of COX-2 under safe concentrations (400, 40, 120, 50 and 400 μM for C1, 17, 20, 22 and 25, respectively) was confirmed on RAW 264.7 cells. Further, in transgenic zebrafish (Danio rerio), significant anti-inflammatory activity at safe concentrations (15, 3, 1.5, 1.5 and 3 μg/mL for C1, 17, 20, 22 and 25, respectively) were observed in a dose-dependent manner. More importantly, molecular docking analysis further revealed the mode of interaction between them and the key active site residues of COX-2. This study screened out and verified unreported COX-2 ligands, potentially accelerating the discovery of new bioactive compounds in other functional foods.

Design, Synthesis, In Silico Study and Anti-Inflammatory Evaluation of New Ketoprofen Thiourea Derivatives

The In the current study, six new derivatives of ketoprofen thiourea were designed and synthesized In order to enhance COX-2 enzyme selectivity. The chemical structures of these derivatives were confirmed by spectral analysis. The anti-inflammatory activities of these derivatives was investigated insilico and in vivo. The results revealed that compound B4 were the most active. The new derivatives also showed drug-likeness and gastric absorption as predicted by computational methods. These results above indicated that the synthesized compounds deserve additional investigation as potential selective COX-2 inhibitors.

Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2-a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors.

Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 μM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 μM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Modification of 4-(4-chlorothiophen-2-yl)thiazol-2-amine derivatives for the treatment of analgesia and inflammation: synthesis and in vitro, in vivo, and in silico studies.

Inflammation is a protective response to a variety of infectious agents. To develop a new anti-inflammatory drug, we explored a pharmacologically important thiazole scaffold in this study. In a multi-step synthetic approach, we synthesized seven new thiazole derivatives (5a-5g). Initially, we examined the in vitro anti-inflammatory potentials of our compounds using COX-1, COX-2, and 5-LOX enzyme assays. After in vitro confirmation, the potential compounds were subjected to in vivo analgesic and anti-inflammatory studies. The hot plate method was used for analgesia, and carrageenan-induced inflammation was also assayed. Overall, all our compounds proved to be potent inhibitors of COX-2 compared to celecoxib (IC50 0.05μM), exhibiting IC50 values in the range of 0.76-9.01μM .Compounds 5b, 5d, and 5e were dominant and selective COX-2 inhibitors with the lowest IC50 values and selectivity index (SI) values of 42, 112, and 124, respectively. Similarly, in the COX-1 assay, our compounds were relatively less potent but still encouraging. Standard aspirin exhibited an IC50 value of 15.32μM. In the 5-LOX results, once again, compounds 5d and 5e were dominant with IC50 values of 23.08 and 38.46μM, respectively. Standard zileuton exhibited an IC50 value of 11.00μM. Based on the COX/LOX and SI potencies, the compounds 5d and 5e were subjected to in vivo analgesic and anti-inflammatory studies. Compounds 5d and 5e at concentrations of 5, 10, and 20mg/kg body weight were significant in animal models. Furthermore, we explored the potential role of compounds 5d and 5e in various phlogistic agents. Similarly, both compounds 5d and 5e were also significantly potent in the anti-nociceptive assay. The molecular docking interactions of these two compounds with the target proteins of COX and LOX further strengthened their potential for use in COX/LOX pathway inhibitions.

New 1,2,4-triazole based eugenol derivatives as antiCOX-2 and anticancer agents

Due to chronic inflammation, elevated cyclooxygenase (COX-2) level leads to tumorigenesis, proliferation, invasion, angiogenesis and metastasis. Therefore, suppression of COX-2 enzyme is a fascinating approach in cancer treatment. In the present study, natural product eugenol was modified to develop new 1,2,4-triazole derivatives as antiCOX-2 and antiproliferative agents. The structures of newly prepared derivatives were established using sophisticated analytical techniques. The antiproliferative result showed compound 10 to be equipotent to doxorubicin towards MDA-MB 231 and PC-3 cancer cells with IC50 1.42 and 5.69 μM, respectively and potent COX-2 inhibitor with IC50 0.28 μM. Compound 10 was also non carcinogenic, non mutagenic with good drug likeness property as depicted by in silico physicochemical and pharmacokinetic studies. The docking results against COX-2 protein showed highest binding energy for compound 10 which was found to be in consistent with the cytoxicity and COX-2 results. In conclusion, compound 10 could harness COX-2 and cell proliferation and could be a promising candidate in cancer therapy.

Identification of potential anti-inflammatory components in Moutan Cortex by bio-affinity ultrafiltration coupled with ultra-performance liquid chromatography mass spectrometry.

Moutan Cortex (MC) has been used in treating inflammation-associated diseases and conditions in China and other Southeast Asian countries. However, the active components of its anti-inflammatory effect are still unclear. The study aimed to screen and identify potential cyclooxygenase-2 (COX-2) inhibitors in MC extract. The effect of MC on COX-2 was determined in vitro by COX-2 inhibitory assays, followed by bio-affinity ultrafiltration in combination with ultra-performance liquid chromatography-mass spectrometry (BAUF-UPLC-MS). To verify the reliability of the constructed approach, celecoxib was applied as the positive control, in contrast to adenosine which served as the negative control in this study. The bioactivity of the MC components was validated in vitro by COX-2 inhibitor assay and RAW264.7 cells. Their in vivo anti-inflammatory activity was also evaluated using LPS-induced zebrafish inflammation models. Finally, molecular docking was hired to further explore the internal interactions between the components and COX-2 residues. The MC extract showed an evident COX-2-inhibitory effect in a concentration-dependent manner. A total of 11 potential COX-2 inhibitors were eventually identified in MC extract. The COX-2 inhibitory activity of five components, namely, gallic acid (GA), methyl gallate (MG), galloylpaeoniflorin (GP), 1,2,3,6-Tetra-O-galloyl-β-D-glucose (TGG), and 1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose (PGG), were validated through both in vitro assays and experiments using zebrafish models. Besides, the molecular docking analysis revealed that the potential inhibitors in MC could effectively inhibit COX-2 by interacting with specific residues, similar to the mechanism of action exhibited by celecoxib. In conclusion, BAUF-UPLC-MS combining the molecular docking is an efficient approach to discover enzyme inhibitors from traditional herbs and understand the mechanism of action.

Synthesis and biological evaluation of new nicotinic acid derivatives as potential anti-inflammatory agents with enhanced gastric safety profile

Two innovative series derived from nicotinic acid scaffold were synthesized and evaluated for their anti-inflammatory activity. Ibuprofen, celecoxib and indomethacin were used as standard drugs. All the newly synthesized compounds were in vitro screened for their anti-inflammatory activity adopting 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide dye (MTT), as well as Griess assays. The results showed that all compounds exhibited significant anti-inflammatory activity without affecting the viability of the macrophages compared to ibuprofen. In addition, compounds 4d, 4f, 4g, 4h and 5b exhibited the most potent nitrite inhibition activity and consequently superior anti-inflammatory activity with MTT results ranging between values 86.109 ± 0.51 to 119.084 ± 0.09. The most active compounds were subjected to evaluation of TNF-α, IL-6, iNOS and COX-2 levels in LPS/INF γ-stimulated RAW 264.7 macrophage cells in comparison to ibuprofen as a reference compound. The five compounds showed comparable inhibition potency of these inflammatory cytokines compared to ibuprofen. Same compounds were further in vivo evaluated for their anti-inflammatory activity via carrageenan induced arthritis in rats. Regarding the ulcerogenic profile, compound 4h showed mild infiltration of gastric mucosa superb to compound 5b displayed severe gastritis. Molecular docking of 4h and 5b in the COX-2 active site was performed to evaluate their preferential COX-2 inhibitory potency. The docking results were in accordance with the biological findings.

Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles.

The development of H2S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H2S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H2S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H2S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.

Design and Evaluation of Synthesized Pyrrole Derivatives as Dual COX-1 and COX-2 Inhibitors Using FB-QSAR Approach.

This study delves into the intricate dynamics of the inflammatory response, unraveling the pivotal role played by cyclooxygenase (COX) enzymes, particularly COX-1 and COX-2 subtypes. Motivated by the pursuit of advancing scientific knowledge, our contribution to this field is marked by the design and synthesis of novel pyrrole derivatives. Crafted as potential inhibitors of COX-1 and COX-2 enzymes, our goal was to unearth molecules with heightened efficacy in modulating enzyme activity. A meticulous exploration of a synthesis library, housing around 3000 compounds, expedited the identification of potent candidates. Employing advanced docking studies and field-based Quantitative Structure-Activity Relationship (FB-QSAR) analyses enriched our understanding of the complex interactions between synthesized compounds and COX enzymes. Guided by FB-QSAR insights, our synthesis path led to the identification of compounds 4g, 4h, 4l, and 4k as potent COX-2 inhibitors, surpassing COX-1 efficacy. Conversely, compounds 5b and 5e exhibited heightened inhibitory activity against COX-1 relative to COX-2. The utilization of pyrrole derivatives as COX enzyme inhibitors holds promise for groundbreaking advancements in the domain of anti-inflammatory therapeutics, presenting avenues for innovative pharmaceutical exploration.

Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies

NSAIDs represent a mainstay in pain and inflammation suppression, and their actions are mainly based on inhibiting COX-1 and COX-2 enzymes. Due to the adverse effects of these drugs, especially on the stomach and heart, scientists efforts have been directed to manufacture selective COX-2 without cardiovascular side effects and with minimal effects on the stomach. The cardiovascular side effects are thought to be related to the chemical composition rather than mechanism of action of these drugs. Novel pyridopyrimidines, 9a-j, were prepared and their chemical structures were confirmed by NMR, mass and IR Spectra, and elemental analysis. The effect of the 9a-j compounds on COX-1 and COX-2 was assessed and it was found that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) was the most potent COX-2 inhibitor (IC50 = 0.54 uM) compared to celecoxib (IC50 = 1.11 uM) with selectivity indices of 6.56 and 5.12, respectively. The in vivo inhibition of paw edema of novel compounds 9a-j was measured using carrageenan-induced paw edema method, and that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) showed the best inhibitory activity in comparison with the other compounds and celecoxib. The gastroprotective effect of the potent derivatives 9d, 9e, 9f, 9 g and 9h was investigated. 2-Hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) and 7-(chlorophenyl)-hydrazino-5-(4-methoxyphenyl)-3H-pyrido[2,3-d)pyrimidin-4-one (9e) showed ulcer indices comparable to celecoxib (1 and 0.5 vs 0.5, respectively). Docking studies were carried out and they confirmed the mechanistic action of the designed compounds Communicated by Ramaswamy H. Sarma

Development of Novel Pyrrole Derivatives and Their Cinnamic Hybrids as Dual COX-2/LOX Inhibitors.

Molecular hybridization has emerged as a promising approach in the treatment of diseases exhibiting multifactorial etiology. With regard to this, dual cyclooxygenase-2/lipoxygenase (COX-2/LOX) inhibitors could be considered a safe alternative to traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs) for the treatment of inflammatory conditions. Taking this into account, six novel pyrrole derivatives and pyrrole-cinnamate hybrids were developed as potential COX-2 and soybean LOX (sLOX) inhibitors with antioxidant activity. In silico calculations were performed to predict their ADMET (absorption, distribution, metabolism, excretion, toxicity) properties and drug-likeness, while lipophilicity was experimentally determined as RM values. All synthesized compounds (1-4, 5-8) could be described as drug-like. The results from the docking studies on COX-2 were in accordance with the in vitro studies. According to molecular docking studies on soybean LOX, the compounds displayed allosteric interactions with the enzyme. Pyrrole 2 appeared to be the most potent s-LOX inhibitor (IC50 = 7.5 μM). Hybrids 5 and 6 presented a promising combination of in vitro LOX (IC50 for 5 = 30 μM, IC50 for 6 = 27.5 μM) and COX-2 (IC50 for 5 = 0.55 μM, IC50 for 6 = 7.0 μM) inhibitory activities, and therefore could be used as the lead compounds for the synthesis of more effective multi-target agents.

Design of potential anti-cancer agents as COX-2 inhibitors, using 3D-QSAR modeling, molecular docking, oral bioavailability proprieties, and molecular dynamics simulation.

Modeling the structural properties of novel morpholine-bearing 1, 5-diaryl-diazole derivatives as potent COX-2 inhibitor, two proposed models based on CoMFA and CoMSIA were evaluated by external and internal validation methods. Partial least squares analysis produced statistically significant models with Q 2 values of 0.668 and 0.652 for CoMFA and CoMSIA, respectively, and also a significant non-validated correlation coefficient R² with values of 0.882 and 0.878 for CoMFA and CoMSIA, respectively. Both models met the requirements of Golbraikh and Tropsha, which means that both models are consistent with all validation techniques. Analysis of the CoMFA and CoMSIA contribution maps and molecular docking revealed that the R1 substituent has a very significant effect on their biological activity. The most active molecules were evaluated for their thermodynamic stability by performing MD simulations for 100 ns; it was revealed that the designed macromolecular ligand complex with 3LN1 protein exhibits a high degree of structural and conformational stability. Based on these results, we predicted newly designed compounds, which have acceptable oral bioavailability properties and would have high synthetic accessibility.

Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized β-Diketone Derivatives as Potent COX-2 Inhibitors.

Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of β-diketones remains largely unexplored. β-Diketones and their complexes find broad applications as biologically active compounds. In this study, in silico molecular docking results revealed that two β-diketone derivatives, namely 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione, exhibit anti-COX-2 activities. However, recent docking results indicated that the relative anti-COX-2 activity of these two studied β-diketones was influenced by the employed docking programs. For improved design of COX-2 inhibitors from β-diketones, we conducted molecular dynamics simulations, density functional theory (DFT) calculations, Hirshfeld surface analysis, energy framework, and ADMET studies. The goal was to understand the interaction mechanisms and evaluate the inhibitory characteristics. The results indicate that 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione shows greater anti-COX-2 activity compared to 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione.

Phytochemical profiling, in vitro analysis for anti-inflammatory, immunomodulatory activities, structural elucidation and in silico evaluation of potential selective COX-2 and TNF-α inhibitor from Hydrilla verticillata (L.f.) Royle

Hydrilla verticillata (L.f.) Royle is a perennial aquatic plant, which exhibits nutritional as well as therapeutic properties. The present study has been carried out to evaluate anti-inflammatory and immunomodulatory activities along with in silico evaluation of potential selective COX-2 and TNF-α inhibitors from methanolic extract of H. verticillata (L.f.) Royle. The potential therapeutic compounds have been identified by high-resolution GC-MS analysis. Its capacity to inhibit inflammatory responses using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells has been explored. The anti-inflammatory properties of the plant extract were investigated by inhibiting inducible nitric oxide (NO) synthase and reduced NO generation driven by LPS on stimulated RAW 264.7 macrophage cells. Further investigation for the underlying molecular mechanism of the anti-inflammatory activity of plant extract has been carried out by molecular docking and molecular dynamics simulation approaches with COX-2 and TNF-α inhibitors ability against the most potent phytocompound phytol from the plant extract. To evaluate whether the extract causes any toxicity, the cytotoxicity test has been carried out with the Human embryonic kidney cell line (Hek-293), Mouse fibroblast (L929), human mesenchyme stem cells (hMSCs) and human breast epithelial cell line (MCF-10a). Ultimately, our findings suggest that the plant extract have great potential to reduce inflammation without causing any toxicity to normal cell. Communicated by Ramaswamy H. Sarma

Water dynamics on the structural properties of some NSAID’s with leucine in the picosecond region using time domain spectroscopy

Concentration-dependent dielectric response for non-steroidal anti-inflammatory drugs (NSAIDs): Aceclofenac (ACF) and Diclofenac (DCF) in the aqueous leucine solution have been reported at different concentrations and temperatures (298.15 K to 283.15 K). The time domain reflectometry technique in the frequency region of 1 GHz to 30 GHz was used for the present study. Complex permittivity (ε*), static dielectric constant (ε), dielectric relaxation time (τ), dipole moment (μ) and Kirkwood correlation factor (g) have been calculated and discussed in terms of the molecular interaction of water and the used drugs. To give more insights into the structural dynamics of drug-induced amino acids, the study includes molar enthalpy of activation (ΔH), entropy of activation (ΔS), and free energy of activation (ΔF). The overall study concludes that the drug (DCF) having a potent inhibitor of cyclooxygenase found a higher static dielectric constant (ε0) than that of the drug (ACF) having more carbon (C), hydrogen (H), and oxygen (O) in the chain, which is more efficient in controlling pain. Communicated by Ramaswamy H. Sarma

Discovering the Active Ingredients of Medicine and Food Homologous Substances for Inhibiting the Cyclooxygenase-2 Metabolic Pathway by Machine Learning Algorithms.

Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase (mPGES-1) are two key targets in anti-inflammatory therapy. Medicine and food homology (MFH) substances have both edible and medicinal properties, providing a valuable resource for the development of novel, safe, and efficient COX-2 and mPGES-1 inhibitors. In this study, we collected active ingredients from 503 MFH substances and constructed the first comprehensive MFH database containing 27,319 molecules. Subsequently, we performed Murcko scaffold analysis and K-means clustering to deeply analyze the composition of the constructed database and evaluate its structural diversity. Furthermore, we employed four supervised machine learning algorithms, including support vector machine (SVM), random forest (RF), deep neural networks (DNNs), and eXtreme Gradient Boosting (XGBoost), as well as ensemble learning, to establish 640 classification models and 160 regression models for COX-2 and mPGES-1 inhibitors. Among them, ModelA_ensemble_RF_1 emerged as the optimal classification model for COX-2 inhibitors, achieving predicted Matthews correlation coefficient (MCC) values of 0.802 and 0.603 on the test set and external validation set, respectively. ModelC_RDKIT_SVM_2 was identified as the best regression model based on COX-2 inhibitors, with root mean squared error (RMSE) values of 0.419 and 0.513 on the test set and external validation set, respectively. ModelD_ECFP_SVM_4 stood out as the top classification model for mPGES-1 inhibitors, attaining MCC values of 0.832 and 0.584 on the test set and external validation set, respectively. The optimal regression model for mPGES-1 inhibitors, ModelF_3D_SVM_1, exhibited predictive RMSE values of 0.253 and 0.35 on the test set and external validation set, respectively. Finally, we proposed a ligand-based cascade virtual screening strategy, which integrated the well-performing supervised machine learning models with unsupervised learning: the self-organized map (SOM) and molecular scaffold analysis. Using this virtual screening workflow, we discovered 10 potential COX-2 inhibitors and 15 potential mPGES-1 inhibitors from the MFH database. We further verified candidates by molecular docking, investigated the interaction of the candidate molecules upon binding to COX-2 or mPGES-1. The constructed comprehensive MFH database has laid a solid foundation for the further research and utilization of the MFH substances. The series of well-performing machine learning models can be employed to predict the COX-2 and mPGES-1 inhibitory capabilities of unknown compounds, thereby aiding in the discovery of anti-inflammatory medications. The COX-2 and mPGES-1 potential inhibitor molecules identified through the cascade virtual screening approach provide insights and references for the design of highly effective and safe novel anti-inflammatory drugs.

Triazole tethered organosilane based fluorescent sensor as a logic gate operation for selective detection of Sn2+ ions: A potent Cyclooxygenase-2 inhibitor

In recent years, the development of a probe for tin ions has gained significant attention due to their relevance in environmental, industrial, and biological contexts. To address this, an imidazole-based fluorescent sensor called BO was designed and synthesized using the click methodology. The characterization of BO was carried out using NMR spectroscopy and mass spectrometry techniques. The fluorescence of BO exhibits remarkable selectivity and sensitivity towards Sn2+ ions, even in the presence of other metal ions. This increase in fluorescence is attributed to the suppression of the PET process upon interaction with Sn2+ ions. Notably, the detection limits for Sn2+ ions using BO in this study are much lower than the drinking water recommendations set by the WHO. Furthermore, it was observed that compound BO displays reversible behaviour towards Sn2+ ions through the formation of the sodium salt of CH3COO–, suggesting its potential application in the construction of a molecular logic gate. Additionally, molecular docking experiments with the Cyclooxygenase-2 (COX-2) protein provided further insights into the potential of BO in this regard.